Tenax LEVEL Trial Misses Primary Goal, but Subgroup Data Bolsters Levosimendan Case

Tenax Therapeutics NASDAQ: TENX reported that its Phase III LEVEL trial of oral levosimendan in patients with pulmonary hypertension associated with heart failure with preserved ejection fraction, or PH-HFpEF, did not meet its primary endpoint, though the company said subgroup, biomarker and hemodynamic findings will inform its next steps in the program. The double-blind, placebo-controlled trial randomized 241 patients across 41 sites in the U.S. and Canada. Participants received oral levosimendan at 1 milligram twice daily for four weeks, followed by 1 milligram three times daily through week 12, or placebo. The primary endpoint was change in six-minute walk distance at week 12. Get Tenax Therapeutics alerts: Sign Up Levosimendan-treated patients recorded a least-squares mean improvement of 14 meters in six-minute walk distance, compared with 10.4 meters for placebo-treated patients. The 3.5-meter difference was not statistically significant, with a p-value of 0.63. The key secondary endpoint, Kansas City Cardiomyopathy Questionnaire total symptom score, also did not reach statistical significance. Subgroup Findings Point to Higher-Burden Patients Chris Giordano, Tenax’s president and chief executive officer, said the company believes the overall result was diluted by enrolling patients with less advanced disease. The median baseline six-minute walk distance in the trial was 333 meters. Among patients with baseline walk distances below that median, levosimendan produced a placebo-corrected improvement of 26.3 meters at week 12, with a nominal p-value of 0.0112. In patients above the median baseline walk distance, the treatment difference was negative 17.6 meters. “We did not fail to find a treatment effect in LEVEL,” Giordano said. “We diluted one.” Stuart Rich, Tenax’s chief medical officer, said the trial’s pre-specified subgroup analyses also showed larger walk-distance treatment differences among older participants and among those with higher baseline NT-proBNP levels, a marker of cardiac wall stress. In patients at or above the median age of 71, the treatment difference was 27.1 meters, while patients in the oldest tertile, above age 74, showed a 37.6-meter difference, according to the company. Rich cautioned that the subgroup p-values were nominal and had not been adjusted for multiple comparisons. The company said it is continuing multivariable analyses. Sanjiv Shah, professor of medicine and director of Northwestern University’s HFpEF program and the trial’s principal investigator, said HFpEF is a heterogeneous condition and that the more severely affected patients may be the ones most likely to benefit from treatment. “The sicker patients really are th...